Regulatory T Cells Shape the Differential Impact of Radiation Dose-Fractionation Schedules on Host Innate and Adaptive Antitumor Immune Defenses

PurposeWe examined how radiation dose per fraction (DPF) and total dose, as represented by biological effective (BED), can independently differentially affect the immunomodulatory capacity of therapy (RT).Methods MaterialsAT3-OVA mammary MC38 colorectal tumors in C57BL/6 mice were irradiated with rationally selected dose-fractionation schedules, alone or immune-modulating -depleting agents. Tumor growth was monitored a readout therapeutic response. Flow cytometry RNA sequencing mouse analysis transcriptomic data sets from human cancers used to examine effects different schedules.ResultsIn AT3-OVA tumors, DPF rather than BED determined ability RT evoke local antitumor CD8+ T cell responses synergize anti-PD-1 therapy. Natural killer cell–mediated control more sensitive BED. Radiation-induced regulatory (Treg) responses, which detected both major factor underlying differential activation adaptive immunity activity natural cells during early phase response RT. Targeted inhibition Treg within rescued enhanced tumor permitted generation abscopal immunologic memory irrespective schedule. did not support induction an amplified highly vulnerable its immunoadjuvant effects.ConclusionsLocal radiation-induced are influenced schedule type critical determinant potential cell–targeted immunotherapy. We (RT). schedules. In effects. Local